Transforming growth factor- (TGF- has a dual role in tumorigenesis, initially functioning as a tumor suppressor and subsequently as a tumor promoter. A fundamental gap in knowledge exists in terms of mechanisms for the dichotomous function of TGF-. The type III TGF- receptor (TRIII) has an emerging yet poorly understood role in regulating TGF- signaling and carcinogenesis. We have establishing that TRIII specifically inhibits cancer cell migration and invasion, in part by undergoing ectodomain shedding, releasing soluble TRIII (sTRIII). To investigate the mechanism of TRIII function, the following hypothesis is proposed: Cell surface TRIII decreases the migration of ovarian surface epithelial cells and ovarian cancer cells by activating Cdc42, disrupting the actin cytoskeleton, focal adhesion formation, polarity and inhibiting directional migration, while sTRIII, generated through MMP-mediated ectodomain shedding, functions to inhibit TGF- signaling and MMP production through a novel Smad1 pathway and TRIII activates Cdc42 to inhibit the invasiveness of breast and ovarian cancer cells. This hypothesis will be addressed by four Specific Aims. Specific Aim 1: The mechanism by which TRIII undergoes ectodomain shedding to produce sTRIII will be established by examining the proteases involved, defining the site(s) of cleavage and how the process is regulated. Specific Aim 2: The mechanism by which TRIII inhibits migration of ovarian surface epithelial cells and ovarian cancer cells will be established by examining the functional elements required for TRIII function, and the effect of TRIII-mediated activation of CDC42 pathways on polarity, directed migration, the actin cytoskeleton and focal complex formation. Specific Aim 3: The mechanism by which TRIII inhibits invasion of breast and ovarian cancer cells will be established by examining the functional elements required for TRIII function, the effect of sTRIII on TGF- cell surface binding, TGF- signaling through Smad1 and MMP production and the effect of TRIII-mediated activation of CDC42 pathways on invasion. Specific Aim 4: The effect of blocking TRIII shedding and sTRIII production, directly decreasing cell surface TRIII and sTRIII expression or expressing TRIII and/or sTRIII on both breast and ovarian cancer cell functions including proliferation, apoptosis, invasion and angiogenesis in vitro and tumor formation and metastasis in vivo will be explored to determine whether cell surface TRIII and sTRIII function in concert to decrease breast and ovarian cancer progression. These studies will define the mechanism by which TRIII inhibits breast and ovarian cancer cell migration and invasion, including the role of ectodomain shedding, define the biological implications of ectodomain shedding of TRIII in the context of human breast and ovarian cancers, and aid in the design of specific interventions for the prevention and treatment of human breast and ovarian cancers and other human cancers in which TRIII has a defined role.